The prevalence of smokeless tobacco use in the US is low vs. cigarette smoking. Yet, rates have remained constant over the past few years, and tobacco companies recently launched new smokeless tobacco products as smoking cessation aids or as alternatives to smoking given bans on smoking in indoor public places. In contrast, the rate of smokeless tobacco use in India is 20%. Smokeless tobacco is carcinogenic and responsible for ~10,000 deaths/year from oral cancer in India. Unfortunately, there have been remarkably few intervention trials in India for smokeless tobacco users. In the US, clinical trials of nicotine replacement therapies (NRTs) and bupropion have yielded null findings. To date, no trial has evaluated the new FDA- approved selective 1422 neuronal nicotinic acetylcholine receptor partial agonist, varenicline, for smokeless tobacco use. Thus, the proposed international collaborative study would enhance research capacity at the National Drug Dependence Treatment Center (NDDTC) at the All India Institute of Medicine in New Delhi and conduct a randomized placebo-controlled trial of varenicline for smokeless tobacco dependence with 250 smokeless tobacco users at the NDDTC in New Delhi. The primary aims of this trial are to: 1) enhance research capacity at the NDDTC (i.e., train and supervise AIIMS staff to implement the behavioral counseling protocol with pharmacotherapy, data collection and management procedures, and participant tracking systems);2) assess the efficacy of varenicline for increasing biochemically confirmed 7-day point prevalence smokeless tobacco quit rates at the end-of-treatment;and 2) assess longitudinal patterns of relapse and recovery following treatment with varenicline. This trial will also explore: 1) changes in withdrawal symptoms, craving, affect, and hedonic effects of smokeless tobacco as mechanisms of varenicline effects;and 2) the role of smokeless tobacco-related (e.g., duration and type of smokeless tobacco), psychological (e.g., depression), and demographic (e.g., gender) variables on response to varenicline to identify those most likely to benefit from varenicline for smokeless tobacco dependence. We propose this clinical trial in India since: 1) smokeless tobacco use is a substantial public health problem in India;2) no pharmacotherapy trials for smokeless tobacco use have been conducted in India;3) participant recruitment will be cost-effective;and 4) we can assess a broad range of moderators of varenicline effects (e.g., gender). The results from this study may support an R01 trial to evaluate long-term treatment effects and additional aims such as cost-effectiveness and mechanisms for the dissemination of results to policy-makers and providers. The proposed study may also yield important information for US smokeless tobacco users since: 1) smokeless tobacco use in the US has remained constant recently and may increase in the coming years;2) NRT and bupropion are ineffective for smokeless tobacco dependence;and 3) varenicline has not been evaluated as a treatment for smokeless tobacco use. PUBLIC HEALTH RELEVANCE: The prevalence of smokeless tobacco use in the US is ~3%, which is far lower than for cigarette smoking. Yet, rates have remained constant over the past few years, and tobacco companies recently launched new smokeless tobacco products as smoking cessation aids or as alternatives to smoking given bans on smoking in indoor public places. In contrast, the rate of smokeless tobacco use in India is 20%. To date, no pharmacotherapy has demonstrated efficacy for smokeless tobacco use in US trials, no pharmacotherapy trials for smokeless tobacco use have been conducted in India, and no clinical trial has evaluated the new FDA- approved medication for tobacco smoke, varenicline, for smokeless tobacco use. Thus, the proposed international collaborative study would enhance research capacity at the National Drug Dependence Treatment Center (NDDTC) at the All India Institute of Medicine in New Delhi and conduct a randomized placebo- controlled trial of varenicline for smokeless tobacco dependence at the NDDTC in New Delhi. The results from this trial will fill several important gaps in the empirical literature, address significant public health concerns for India and the US, and facilitate additional research studies in India.